Blood is a highly complex liquid with many components and a variety of functions, the most important of which include transport of oxygen and metabolic substances to tissues, removal of carbon dioxide and metabolic products, and maintenance of the concentration of ions and other solutes in the extracellular fluids. Ischemia results from a lack of blood flow to the affected tissues. Such tissues show reduced function, and may be permanently damaged, or may even die. Ischemic modifiers, such as perfluorocarbon chemical emulsions, function to provide oxygen to tissues made ischemic by lack of blood flow. In so doing, they promote near normal or enhanced tissue function, hence they act as ischemic modifiers. In 1966, Leland C. Clark, Jr. of the University of Cincinnati College of Medicine, demonstrated the high oxygen solubility of perfluorochemicals. Normal saline or blood plasma dissolves about 3 volume percent oxygen and whole blood about 20 volume percent oxygen. In contrast, perfluorochemicals dissolve about 40 volume percent or more of oxygen. In addition, perfluorocarbon compounds dissolve even more carbon dioxide.
Since 1966, a number of investigators have worked on the development of perfluorocarbon chemical formulations as blood substitutes and a ischemic modifiers. The perfluorocarbon chemical formulations normally comprise an emulsion of perfluorocarbon chemicals in an aqueous media. For biological purposes, these emulsions may also contain electrolytes, such as sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium bicarbonate and metabolites, such as glucose. A discussion of perfluorocarbon chemical emulsions is set forth in PERFLUOROCHEMICAL BLOOD SUBSTITUTES (FC-43 EMULSION) (FLUOSOL.RTM.-DA, 20% and 35%) (FLUOSOL.RTM. is a registered trademark of Alpha Therapeutic Corporation, Los Angeles, Calif.) FOR PRECLINICAL STUDIES AS A CANDIDATE FOR ERYTHROCYTE SUBSTITUTION BY R. NAITO AND K. YOKOYAMA; Technical Information Ser. No. 5; June 30, 1978, revised July 1, 1981; The Green Cross Corporation, Osaka, Japan and PERFLUOROCHEMICAL BLOOD SUBSTITUTES (FC-43 EMULSION) (FLUOSOL.RTM.-DA, 20%, 35%) AS AN OXYGEN-CARRYING COLLOIDAL BLOOD SUBSTITUTE; Technical Information Ser. No. 7; July 30, 1981; The Green Cross Corporation, Osaka, Japan. The disclosure of both these publications is incorporated herein by reference.
Perfluorochemical emulsion formulations are normally supplied in plastic bags which are gas-permeable. Accordingly, perfluorochemical emulsion formulations are not oxygenated at the time of packaging, since the oxygen in the bag can diffuse out through the plastic bag and the nitrogen in the air can diffuse into the plastic bag to obtain an equilibrium gas mixture inside and outside the bag. In practice, the perfluorochemical emulsion formulation is oxygenated at a time just prior to use.
Previous methods used for oxygenation of perfluorocarbon emulsion formulations include bubbling an oxygen containing gas, such as a mixture of 95% oxygen and 5% carbon dioxide by volume (medical oxygen commonly called carbogen), through the perfluorocarbon emulsion while it is in its plastic bag. Another method is to remove a portion of the perfluorocarbon emulsion from the bag, place it into another container, bubble the oxygen containing gas through it and then return it to the plastic bag. Finally, perfluorocarbon emulsions have been oxygenated by passing them through an oxygenation device such as a membrane oxygenator. Although the above described prior art methods are all effective in oxygenating blood substitutes to an adequate partial pressure of oxygen, (pO.sub.2), they can compromise the sterility or integrity of the product in one manner or another or are inconvenient to use in a hospital setting.
A simple and inexpensive method and apparatus is needed for enabling a medical practitioner to oxygenate perfluorochemical emulsion formulations in the bag so that the final product is sterile and attains a predictable pO.sub.2 upon oxygenation.